<scp>HLA</scp> alleles and <scp>HLA‐B27</scp> haplotypes associated with susceptibility and severity of ankylosing spondylitis in a Portuguese population

Pimentel-Santos, Fernando; Matos, Maria Margarida Nunes Gaspar de; Ligeiro, Dário; Mourão, Ana Filipa; Ribeiro, Cristina; Costa, José António; Santos, Helena; Barcelos, Anabela; Pinto, Patrícia; Cruz, Margarida; Sousa, E.; Santos, Renata; Fonseca, João Eurico; Trindade, Hélder; Guedes-Pinto, Henrique; Branco, Jaime

doi:10.1111/tan.12238

Cited by 19 publications

(13 citation statements)

References 33 publications

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“…The highly polymorphic amino acid chains of DQB1 are capable of forming the peptide binding groove that presents antigen to CD4 + T-helper cells [27], and controlling the immune response [28, 29]. Previous studies reported that HLA-DQB1 was associated with radiographic severity in AS [30, 31]. The different alleles of HLA-DQB1 were also associated with the age of AS onset [31].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation profile analysis identifies differentially methylated loci associated with ankylosis spondylitis

Hao

Yang²,

et al. 2017

Arthritis Res Ther

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BackgroundAnkylosing spondylitis (AS) is a chronic rheumatic and autoimmune disease. Little is known about the potential role of DNA methylation in the pathogenesis of AS. This study was undertaken to explore the potential role of DNA methylation in the genetic mechanism of AS.MethodsIn this study, we compared the genome-wide DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) between five AS patients and five healthy subjects, using the Illumina Infinium HumanMethylation450 BeadChip. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was performed to validate the relevance of the identified differentially methylated genes for AS, using another independent sample of five AS patients and five healthy subjects.ResultsCompared with healthy controls, we detected 1915 differentially methylated CpG sites mapped to 1214 genes. The HLA-DQB1 gene achieved the most significant signal (cg14323910, adjusted P = 1.84 × 10–6, β difference = 0.5634) for AS. Additionally, the CpG site cg04777551 of HLA-DQB1 presented a suggestive association with AS (adjusted P = 1.46 × 10–3, β difference = 0.3594). qRT-PCR observed that the mRNA expression level of HLA-DQB1 in AS PBMCs was significantly lower than that in healthy control PBMCs (ratio = 0.48 ± 0.10, P < 0.001). Gene Ontology (GO) and KEGG pathway enrichment analysis of differentially methylated genes identified four GO terms and 10 pathways for AS, functionally related to antigen dynamics and function.ConclusionsOur results demonstrated the altered DNA methylation profile of AS and implicated HLA-DQB1 in the development of AS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1382-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation profile analysis identifies differentially methylated loci associated with ankylosis spondylitis

Hao

Yang²,

et al. 2017

Arthritis Res Ther

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“…These conformational changes are caused by the binding of variety of peptides to alleles of MHC II. In addition, the associations of MHC II alleles with various diseases have been previously reported [17], [18], [19].…”

Section: Introductionmentioning

confidence: 92%

Chronic Beryllium Disease: Revealing the Role of Beryllium Ion and Small Peptides Binding to HLA-DP2

Petukh

Stefl

et al. 2014

PLoS ONE

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Chronic Beryllium (Be) Disease (CBD) is a granulomatous disorder that predominantly affects the lung. The CBD is caused by Be exposure of individuals carrying the HLA-DP2 protein of the major histocompatibility complex class II (MHCII). While the involvement of Be in the development of CBD is obvious and the binding site and the sequence of Be and peptide binding were recently experimentally revealed [1], the interplay between induced conformational changes and the changes of the peptide binding affinity in presence of Be were not investigated. Here we carry out in silico modeling and predict the Be binding to be within the acidic pocket (Glu26, Glu68 and Glu69) present on the HLA-DP2 protein in accordance with the experimental work [1]. In addition, the modeling indicates that the Be ion binds to the HLA-DP2 before the corresponding peptide is able to bind to it. Further analysis of the MD generated trajectories reveals that in the presence of the Be ion in the binding pocket of HLA-DP2, all the different types of peptides induce very similar conformational changes, but their binding affinities are quite different. Since these conformational changes are distinctly different from the changes caused by peptides normally found in the cell in the absence of Be, it can be speculated that CBD can be caused by any peptide in presence of Be ion. However, the affinities of peptides for Be loaded HLA-DP2 were found to depend of their amino acid composition and the peptides carrying acidic group at positions 4 and 7 are among the strongest binders. Thus, it is proposed that CBD is caused by the exposure of Be of an individual carrying the HLA-DP2*0201 allele and that the binding of Be to HLA-DP2 protein alters the conformational and ionization properties of HLA-DP2 such that the binding of a peptide triggers a wrong signaling cascade.

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“…The mechanisms leading to AS are unknown, although human leukocyte antigen B27 (HLA-B27) is known a major risk factor for AS [5]. HLA-B27 is known a genetic marker present in 90%–95% of AS patients [6].…”

Section: Introductionmentioning

confidence: 99%

A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

Yang

Wang

et al. 2016

IJMS

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Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. However, the precise factors that determine one’s susceptibility to AS remain to be unraveled. With 100 trillion bacteria residing in the mammalian gut having established a symbiotic relation with their host influencing many aspects of host metabolism, physiology, and immunity, a growing body of evidence suggests that intestinal microbiota may play an important role in AS. Several mechanisms have been suggested to explain the potential role of the microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. In this review, the existing evidence for the involvement of the microbiome in AS pathogenesis was discussed and the potential of intestinal microbiome-targeting strategies in the prevention and treatment of AS was evaluated.

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HLA alleles and HLA‐B27 haplotypes associated with susceptibility and severity of ankylosing spondylitis in a Portuguese population

Cited by 19 publications

References 33 publications

Genome-wide DNA methylation profile analysis identifies differentially methylated loci associated with ankylosis spondylitis

Genome-wide DNA methylation profile analysis identifies differentially methylated loci associated with ankylosis spondylitis

Chronic Beryllium Disease: Revealing the Role of Beryllium Ion and Small Peptides Binding to HLA-DP2

A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

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